Abstract
Microglia have become a therapeutic target of many inflammation-mediated diseases in the central nervous system (CNS). Recently, microRNA (miRNA) has been proposed as an important regulator of immune responses. Specifically, miRNA-129-5p has been shown to play critical roles in the regulation of microglia activation. We have demonstrated that biodegradable poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) modulated innate immune cells and limited neuroinflammation after injury to the CNS. In this study, we optimized and characterized PLGA-based NPs for miRNA-129-5p delivery to utilize their synergistic immunomodulatory features for activated microglia modulation. A series of nanoformulations employing multiple excipients including epigallocatechin gallate (EGCG), spermidine (Sp), or polyethyleneimine (PEI) for miRNA-129-5p complexation and miRNA-129-5p conjugation to PLGA (PLGA-miR) were utilized. We characterized a total of six nanoformulations through physicochemical, biochemical, and molecular biological methods. In addition, we investigated the immunomodulatory effects of multiple nanoformulations. The data indicated that the immunomodulatory effects of nanoformulation, PLGA-miR with the excipient Sp (PLGA-miR+Sp) and PEI (PLGA-miR+PEI) were significant compared to other nanoformulations including naked PLGA-based NP. These nanoformulations promoted a sustained release of miRNA-129-5p and polarization of activated microglia into a more pro-regenerative phenotype. Moreover, they enhanced the expression of multiple regeneration-associated factors, while alleviating the expression of pro-inflammatory factors. Collectively, the proposed nanoformulations in this study highlight the promising therapeutic tools for synergistic immunomodulatory effects between PLGA-based NPs and miRNA-129-5p to modulate activated microglia which will have numerous applications for inflammation-derived diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 3439-3452 |
| Number of pages | 14 |
| Journal | Nanoscale Advances |
| Volume | 5 |
| Issue number | 13 |
| DOIs | |
| State | Published - May 5 2023 |
Bibliographical note
Publisher Copyright:© 2023 RSC.
Funding
This work was supported by the Center for Pharmaceutical Research and Innovation (CPRI, NIH P20 GM130456), the National Center for Advancing Translational Sciences (UL1 TR001998), and the University of Kentucky Neuroscience Research Priority Area (NRPA017). The authors thank Larissa Ponomareva for the assistance with the Cytation 7 plate reader and Svitlana Rudik for the graphic abstract.
| Funders | Funder number |
|---|---|
| University of Kentucky Neuroscience Research Priority Area | NRPA017 |
| National Institutes of Health (NIH) | P20 GM130456 |
| National Center for Advancing Translational Sciences (NCATS) | UL1 TR001998 |
| Center for Pharmaceutical Research and Innovation, University of Kentucky |
ASJC Scopus subject areas
- Bioengineering
- Atomic and Molecular Physics, and Optics
- General Chemistry
- General Materials Science
- General Engineering